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For 4 years now, I have been on a good working combo of Kivexa (=Epzicom) and Kaletra. No side effects, lipids are fine. CD4s increased from 0 to 480 and I have been UD since 3,5 years. However, CD4 % do not really improve and linger around 0,15-0,2 due to a massive number of CD8. It's the permanent activation of the immune systems which my doc doesn't like.

Now, to reduce the permanent activation, to lower CD8 numbers and thus to improve the CD4/(CD4+CD8) ratio, my doc suggests adding Selzentry as a third drug (actually a fourth, since Kivexa is double). Apparently, there are new studies which claim that Selzentry has a beneficial effect on CD4 %. We already did a tropism test and it confirmed that my viral buddy is highly sensitive to CCR5-inhibitors. After 8 weeks of intensified combo he wants to check whether it works. If it does, he wants to quit the Kivexa, leaving me with a double combo Selzentry and Kaletra.

What do you think about this? Do you have experiences with Selzentry as a tool to decrease CD8 levels and to improve the ratio? Is a double combo of Selzentry and Kaletra a viable option?

This thread is HIGHLY INTERESTING, because it is one (rare) case of intervention in order to address this issue (in the context of a larger issue:why do some people do not regain full immune system ?).

Some people also think that HIV triggers inflammation which causes the death of CD4s, and so on.

In an adverse environment, if CD4 have a shorter life expectancy and the system can only supply so many CD4, then the total population of CD4 is not as high as one would otherwise expect.

Look at CD8s as being land mines or bombs and remember those simple video games such as Window mines or BomberMan.

If the mines are too many, the chances that a CD4 can get in a mature stage is less than if it dwells in a sea more free of this dangerous species.

So when you are on your way to recovery, doc will look at : in order of 'urgency':

CD4 countCD4 % thenCD4 to CD8 ratio

pretty much as when you are helping someone out of bankruptcy you look at :- improving immediately available cash- improving cash/needs-for-cash ratio (cash flow)and then if your recovery is on the right track will they consider what your long term financial ressources are made of (such as stocks/bonds ratio)

So question of CD8 is LESS critical in terms of CLINICAL management, but in terms of chronic management, not having a full recovery is a cause of concern.

The concerns expressed by Cerrid's doc is very legitimate in terms of chronic management and time line (once again this CD8 question is NOT for people at death door...)

In HIV negs and otherwise healthy people, the CD4 to CD8 ratio is between 1 and 2. In HIVERS (no meds) it is much lower (my lowest was 0.25, it is now 0.78 , I even has a peak at 0.88 at month 5)

The interesting approach of his doc is to assume that a meds intervention can help the situation.

And it makes sense in a certain context of thoughts.

Meds act at different stages of viral life cycle.

Newly developed meds (integrase inhibitors, entry inhibitors) work earlier in the viral life cycle so his doc expectation is that by acting earlier, this would protect the CD4 more from HIV (or to be precise, HIV triggered signals for cell suicide)

which would reduce inflammation, which would improve CD4 life expectancy and so forth.

It is an egg and chicken issue here : which is the original cause

His doc is taking one approach : protect the CD4 in order to reduce inflammation

This other side would be : reduce inflammation in order to protect CD4s.

We already did a tropism test and it confirmed that my viral buddy is highly sensitive to CCR5-inhibitors.

Hi Cerrid

Could explain where/how this was made. I thought that one would need a detectable level of at least 1000 in order to perform that tropism test. This field is moving so fast. May be I am out dated on this one...

thanks for your reply. Indeed, the main motivation is to reduce the underlying chronic inflammation - not only to save the CD4, but also because it is believed to be a risk factor for cardiovascular diseases and other longterm nastinesses. I'm pretty excited too how this little experiment turns out. The first evaluation is in three months time. My HIV doc visits all major AIDS conferences and is permanently in discussions with his colleagues about new approaches to improve the life of his patients. When I'm in his office, we always chitchat about new studies and stuff, so that's a pretty good basis.

Now, for the tropism test: There are two methods to do it. The first one is the standard phenotype test called "Trofile". It's very sensitive and gives very accurate results. But you have to have more than 1000 viral copies/ml which may be alright if you're untreated, but not very practical when you're already undetectable and plan future combo switches.

Then there's a newer method, the genotypic tropism test. Since it works with proviral DNS, it requires a much lower VL, down to the undetectable level. Results are then calculated via the geno2pheno analysis. The genotype analysis is cheaper than the phenotype analysis and is about to replace it, at least in Europe. Here's a brand new guideline on genotypic tropism tests recommended by European virologists with some additional footnotes. I have no idea if this recommendation has reached US docs or whether there are any labs who offer genotype testing, so maybe you have to ask your doc yourself.

Myself, I was very interested in Maraviroc in the first place, but apparently, here, it is still reserved for treatment experienced people and not for treatment naives.

My doc was not too much in favor of it because he runs a HIV clinic (as a private practice) and I guess he is limited to 'standard procedures'. Whenever he needs to go to 'advanced procedures', he then has to refer back to his 'alma mater' hospital.The science is moving fast here and he took a conservative approach. Apparently, the only way to get maraviroc as treatment naive was to enter a trial (I did try,but failed the requirements...)

Anyway, I am keeping a close eye on it because this approach is so far, in my views, the closest there is to the procedure undergone by the Berlin patient. That is prevent the virus to enter cells altogether rather than jam its replication while as it has already entered the cell.

We all know that it is much better when the virus is not allowed not enter in the first place, alas...

At that time (6 months ago) my doc also mentioned that newer entry inhibitors where being developed that, hopefully, would have a better profile.

Anyway, he underwent his own little experiment on me, initiating me on meds that are fairly 'old' (I am his first treatment naive he initiates with this combo ! - viramune + Kivexa)

On this forum, a good number of people are getting quite fast to UD and are also , mostly happy with their immune recovery.

There are other groups:- non responder (they have to switch (resistance, SE, etc...), but ultimately find a regimen that works for them- slow virologic responder (VL declines only slowly, such as myself)- good virologic responder but with an immune system recovery that leaves room for improvement (should I count yourself in this group? - I am almost certain you went UD very fast)

There are a number of studies (and posters in this forum) that show that slow virologic response does not predict a poorer immunologic response.Actually I found much encouragement in that a number of posters with slow virologic response had in fact a strong immune recovery on the long run.This is my case.

In other words, (everyone being different...), in that respect my case mirrors yours in that it is almost an opposite.

As you know, virologic response comes first in meds decisions and I was at the same time very worried (slow virologic response) and very happy with the immunologic response.

I have tried to understand the underlying mechanisms, with the belief that what explains my situation may shed light on situations like yours and vice versa.

In the egg-chicken situation, you're on one side of the coin and I am on the other side. And I hope to get down to the bottom of it, not just for my own satisfaction, but because, this may help OTHERS.

This is why I am so excited about this (your 'little' experiment) because, being a complete novel approach, it adds value to current thinking.

I think that studying why some people have a better (virtually perfect) defense against HIV has helped understand what happens to those who do not have that luxury. (hence the delta switch thing and the Berlin patient)

I also hope that understanding why some people have a good immunologic recovery can help those who do not have that luxury...

I am working on it... And I think, but this is just a hunch (as far as I am concerned) that the key guys are those CD8s (and more precisely the activated CD8, I think there is a sub population named CD38 or something...), Anyway...

Reflecting on the life expectancy of CD4s and CD8s, I found academic papers that are consistent with the idea that CD8s have a longer half life (life time - life expectancy) than CD4s.

and one of the reasons why your CD8 % is high could (emphasized could) be that your CD8s half life is ... longer than in most people.

If this is the case, then your Maraviroc intervention, albeit successfull, may not show its full results within 8 weeks only.

That would be my only reservation on your project, namely you guys might declare it unsuccessful not because it is but because you have not allocated enough time.

Whichever way it goes: if you are successful, it will provide immediate keys to help people in similar situation.If you are not, then reflecting on the causes and trying something else will take more time, but I see resolve in your (and your doctor's) approach and I am very hopefull that success will prevail, one way or another.

It is very helpful to have something to look forward to.

And whereas I have spent that last 6 months in a (somewhat selfish) exhausting wait for a positive outcome, I am happy that your thread has initiated a new thing to look forward to : the success of YOUR plans.

Seems a cool pathway to stamp the virus out. I am a bit worried of those meds getting INTO the cells and messing up with other natural processes into order to jam the virus life cycle INTO the cell.

I do not think that any genetic therapy or other similar intervention such as the one undergone by the Berlin patient are for 2011-2015 (may be available, but not in the next 5 years). Entry inhibitors are the closest thing to it on the table at this time.

At this point Cerrid's project is a enhancement procedure, so it is safe. Down the road, dropping Kivexa in a dual Selzentry/PI combo could be considered, but this is something that may come up at a later stage of the intervention.

I would personally prefer a more potent PI as a backbone, but this discussion is too early, at this point.

Surf,

I have tried to answer your question on the role of CD8 in layman's language and I hope it helps understand why the focus is moving from CD4 to CD8 ONCE the VL is under control and some tweaking is desired.

and yes, the OP relates to you also. What is your experience with Maraviroc with regards to CD4 recovery for starters and with regards to CD4 / CD8 ratio (or CD4 to (CD4+CD8) ratio) as this is the matter raising concern in cerrid's journey to full recovery.

You were saying that you have a similar concern. Do you have your recovery pattern described somewhere ?

Your personal experience with regards to the issue discussed here would help construct a fruitfull discussion here.

CD4% is still expected to go up in the next 6-12 monthsAlongside which CD8 % is expected to go down. You are still in a phase where things should normally adjust.Your CD8% is, hopefully, only temporarily high.

Give it time. Cerrid's case, in that respect, is different. After 3 years he is getting the expected but not to full extend.Cerrid's CD8% are, unfortunately, chronically high.

Why doesn't he just switch you to Truvada from Kivexa to start? It is likely that, by some unknown action, the abacavir in Kivexa contributes to inflammation (as per the DAD findings on heart attack), and anyway, can he or anyone else tell you, apart from that it happens, that CD8 activation is a benefit or disbenefit in HIV-positive people (answer: in terms of outcomes, no). An aspirin a day might just do the trick too.

I would be very wary of the 2 drug combo suggested, personally, it has no decent research base on outcomes, it's an experiment.

Based on the numbers in these studies, the immune modulating effects of maraviroc are somewhat overstated. It is seems no better and no worse than other combinations/drugs at raising CD4 count. The picture on CD8 count is completely unclear, in some trials CD8 count went up, in others down and sometimes this just stayed the same.

when i get home tonight ill have to pull out all my blood records and see where these cd8 fallsinteresting.i have a feeling he did this drug combo becasue a- the veramune rash and b- my being clear on lipo issues

any other numbers i should look up while i have the records out?thanks for hte info

abacavir in Kivexa contributes to inflammation (as per the DAD findings on heart attack)

Since I take Abacavir I did a bit of research on that additional risk for heart attacks with abacavir. On the top of my mind there are as many studies to claim there is a risk as there are that claim there is not.

A very recent one studied the interest of treatment enhancement by abacavir:

I have my first appointment with the cardiologist (who specializes in HIVers) next week and I will discuss the issue.

Any med has some kind of additional risk on something... Short term risk of Abacavir may be more significant than Tenofovir, due to the hypersensitivity reaction, which is now very much reduced now that there is this HLBA XXXX (whatever) screening test) Long term risks on Abacavir are apparently limited to the heart. Long term risk associated with Tenofovir are associated with bone density loss and renal failure.

So it is hard to say which is best.

One question I will ask the cardiologist, though, is whether serious monitoring of the heart condition can be effective (predictive/preventive, etc.) when using Abacavir, in other words whether Abacavir induces a manageable risk or a sudden failure that can not be reduced by whatever method. And I'll report what he says...

The CD4 to CD8 ratio which is between 1 and 2 in HIV negatives, is much lower under HIV infection (my lowest was 0.25). It should restore somewhat. It may take time to restore. Mine is at 0.8 at month 5 and my doc anticipated that it would/should reach 1.0 within the next 12 months.

It is a concern if the ratio does not 'restore' to a certain level (I mean it does not HAVE to retore to 1, or in other words, I did not meant that is HAS to restore to 1) after YEARS of treatment. The fact that the ratio remains below 1 after MONTHS of treatment is not a major concern.

And please kindly bear in mind that finding means to restore that ratio is still a subject for research.

So, with regards to your (Surf) position on the timeline and your CD4/C8 ratio, the issue is different and not a matter of concern, whereas it is for Cerid, because, he is already YEARS into treatment.

..but is outside guidelines and experimental. Each to their own, some will, some won't. Given we are all an experiment, me personally, the less unknowns the better.

And Eric, I do need to say, if you are gonna make sweeping statements about abacavir v tenofovir and long-term side effects perhaps some prevalence data would be helpful/reassuring. The picture on abacavir and cardiovascular risk is complex (but true to a degree), and the picture on tenofovir not as bleak as you suggest earlier (but also true to a degree).

The time I can devote to collect papers/articles and other data is quite used up by researching on the concerns of mine, and I am generally not commenting on meds I do not take.

I let everyone do their own research... I am not a Librarian

Please kindly do me the favor to consider that, while I may make mistakes in understanding such a complex issue, I also do my best not to make things up out of the blue.

there is a recent focus on CD8 and activated CD8, in certain circumstances and certain settings. Whether this is justified or not, history will tell...

There are a number of reasons why I say there is an increased interest in research community on the matter of CD8 (and specifically elevated CD8 after several years of treatment) and I can list a few:

1- this very OP2-http://retroconference.org/2010/Abstracts/39346.htm and its conclusion:Strategies to decrease CD8 activation in this setting are worth pursuing.3-http://www.ncbi.nlm.nih.gov/pubmed/20126452

One of the most common concern of infected people is whether medical treatment can get them back to their pre-infection condition (which they do not really know...). Hence a umbrella concept of restorationbe it restoration of one's life expectancy, CD4 count, CD4% and other markers. Since these are unknowns (for most people), one way of assessing one's restoration is when one's ratio are getting closer to what is observed in the general population. The closer their ratio is to the 'norm', the happier most people will be. Some others don't mind... It is just a general feeling I have that most people (including the medical community) would consider that if a given maker remains far off the 'norm' (be it TG, HDL, etc.), then it is a 'concern'.

If you would want to discuss the relative importance of CD4/CD8 ratio restoration I would suggest you ask the specialists around you. (and not me...)

As for myself, I have... (and I am not the only one in the forum to have) discussed it with my doctor who told me that the CD4 to CD8 ratio improvement is something he looks at, not as a primary goal, but more as a cherry on the cake.

Back to the Abacavir added risk to MI, it is indeed a concern of mine. I am not too happy with this additional risk. Therefore I will discuss it with the cardiologist.

That being said, I admit that the combo switch which is discussed here is 'experimental', but unlike some other discussions I have read recently, it is under close medical supervision. I would not say that I would be happy to be in Cerid shoes or would encourage the switch itself, I would certainly encourage that he posts his findings/results.